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Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells.

Published version
Peer-reviewed

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Authors

Gonçalves, Emanuel 
Sciacovelli, Marco 
Costa, Ana SH 
Tran, Maxine Gia Binh 
Johnson, Timothy Isaac 

Abstract

Deregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in fumarate hydratase (FH) deficient cells and developed a computational modelling approach to identify putative regulatory phosphorylation-sites of metabolic enzymes. We identified previously reported functionally relevant phosphosites and potentially novel regulatory residues in enzymes of the central carbon metabolism. In particular, we showed that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells, restricting carbon entry from glucose to the tricarboxylic acid cycle. Moreover, we confirmed PDHA1 phosphorylation in human FH-deficient tumours. Our work provides a novel approach to investigate how post-translational modifications of enzymes regulate metabolism and could have important implications for understanding the metabolic transformation of FH-deficient cancers with potential clinical applications.

Description

Keywords

Cancer, Metabolism, Modelling, Phosphoproteomics, Cell Line, Tumor, Fumarate Hydratase, Humans, Neoplasm Proteins, Neoplasms, Protein Processing, Post-Translational, Pyruvate Dehydrogenase (Lipoamide)

Journal Title

Metab Eng

Conference Name

Journal ISSN

1096-7176
1096-7184

Volume Title

45

Publisher

Elsevier BV
Sponsorship
MRC (unknown)
Medical Research Council (MC_UU_12022/6)